RESUMEN
At therapeutic dose, loperamide is a safe over-the-counter antidiarrheal drug but could induce cardiotoxic effect at a supratherapeutic dose. In this study, we use cardiac and oxidative biomarkers to evaluate loperamide-induced cardiotoxicity in rats. Rats were orally gavaged with 1.5, 3, or 6 mg/kg body weight (BW) of loperamide hydrochloride for 7 days. The results after 7 days administration of loperamide, revealed dose-dependent increase (P < 0.05) in aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, and serum concentration of cardiac troponin I, total homocysteine, and nitric oxide. A 50% decrease in antioxidant enzymes activity was observed at 6 mg/kg BW. Furthermore, malondialdehyde and fragmented DNA also increased significantly in the heart of the treatment groups. Loperamide provoked cardiotoxicity through oxidative stress, lipid peroxidation, and DNA fragmentation in rats. This study has provided a possible biochemical explanation for the reported cardiotoxicity induced by loperamide overdose.
Asunto(s)
Antidiarreicos/toxicidad , Biomarcadores/sangre , Corazón/efectos de los fármacos , Loperamida/toxicidad , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Aspartato Aminotransferasas/sangre , Catalasa/metabolismo , Forma MB de la Creatina-Quinasa/sangre , ADN/metabolismo , Glutatión/metabolismo , Glutatión Transferasa/metabolismo , Corazón/anatomía & histología , L-Lactato Deshidrogenasa/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Proteínas Musculares/metabolismo , Miocardio/enzimología , Oxidación-Reducción , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
We investigated the mechanism of lophirones B- and C-mediated protection against acetaminophen hepatotoxicity. Mice were pretreated with 20 mg/kg body weight lophirones B and C for 7 days and challenged with acetaminophen on day 7. Acetaminophen raised nuclear factor-κB (NF-κB) in the liver of mice but lowered protein kinase B (Akt). Although, acetaminophen produced no significant alteration on nuclear erythroid related factor-2 (Nrf-2), phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC), lophirones B and C raised the level of these proteins and Akt. The acetaminophen-mediated increase in NF-κB was significantly reversed by lophirones B and C. Lophirones B and C prevented acetaminophen-mediated alterations in serum biomarkers of hepatic injury. Similarly, lophirones B and C lowered the biomarkers of oxidative stress in the liver of acetaminophen-treated mice. It can be inferred from this study that lophirones B and C prevent acetaminophen-induced liver injury by enhancing Nrf-2 through Akt, PI3K, and PKC pathways.
